Heat shock protein (HSP) overexpression in lung cancer and potential as a therapeutic target

Proc Amer Assoc Cancer Res, Volume 46, 2005 2387 Heat shock proteins (HSPs) are molecular chaperones that play a central role in the ability of cells to survive external stresses. Many cancers have been found to express high levels of heat shock proteins (such as HSP 10, 27, 60, 70, 90, and 110). Certain HSPs, such as HSP27, HSP70, and HSP90 are of particular interest for further investigation as they have antiapoptotic properties, chaperone important signaling molecules such as Akt, erbB2, Raf-1, HIF-1α, c-Met (HSP90), and have immunostimulatory properties that can be exploited for vaccine strategies (HSP70). Early drugs targeting HSPs are currently in phase I/II clinical trials (e.g. 17-AAG and STA-4783). We investigated the role of heat shock proteins in lung cancer tissues and sera from patients and tested HSP70 modulation using STA-4783, a novel HSP70 inducer. Using standard immunohistochemistry, we were able to show over-expression of HSP10, HSP27, HSP47, HSP60, HSP70, and HSP90 in the majority of tumor tissues from both small cell lung cancer (SCLC) and non-SCLC (NSCLC) as compared to adjacent normal parenchyma/stroma. Majority of the HSP expression was cytoplasmic; in addition nuclear staining was seen in HSP70 (strong) and also in HSP90 (weak). Correlation with clinical outcomes is currently ongoing. Serum analysis of HSP70 from SCLC patients showed increased circulating levels of HSP70 as compared to normal control sera. In particular, the levels of HSPs were elevated in extensive stage and relapsed SCLC as compared to limited stage SCLC. HSP70 serum levels correlated with disease state in SCLC and levels were as follows [value+SD, in ng/ml]: Normal control 6.4+1.3; Limited Stage 11.2+3.1; Extensive Stage 15.4+3.3; No Evidence of Disease 11.4+2.1; and Recurrent Disease 19.4+5.0. Finally, modulation of HSP70 using STA-4783 leads to cell surface localization in A549 and Calu-1 NSCLC cells, and less dramatically in H69 SCLC cells. Changes in HSP70 localization expression correlated with cytoskeletal reorganization, consisting of rearrangement of the microtubule and microfilament networks. Hence, investigations of HSPs as potential tumor biomarkers and therapeutic targets are promising in lung cancer.